Showing papers on "Toxicity published in 1988"

Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer.

Abstract: Studies in animals suggest that the bispiperazinedione ICRF-187 can prevent the development of dose-related doxorubicin-induced cardiac toxicity. In a randomized trial in 92 women with advanced breast cancer, we compared treatment with fluorouracil, doxorubicin, and cyclophosphamide (FDC), given every 21 days, with the same regimen preceded by administration of ICRF-187 (FDC + ICRF-187). Patients were withdrawn from the study when cardiac toxicity developed or the cancer progressed. The mean cumulative dose of doxorubicin tolerated by patients withdrawn from study was 397.2 mg per square meter of body-surface area in the FDC group and 466.3 mg in the FDC + ICRF-187 group (no significant difference). Eleven patients on the FDC + ICRF-187 arm received cumulative doxorubicin doses above 600 mg per square meter, whereas one receiving FDC was able to remain in the study beyond this dose. Antitumor response rates were similar (FDC vs. FDC + ICRF-187, 3 vs. 4 complete responses; 17 vs. 17 partial responses; and 9.3 vs. 10.3 months to disease progression). Although myelosuppression was slightly greater in the FDC + ICRF-187 group, the incidence of fever, infections, alopecia, nausea and vomiting, or death due to toxicity did not differ between the groups. Cardiac toxicity was evaluated by clinical examination, determination of the left ventricular ejection fraction by multigated nuclear scans, and endomyocardial biopsy. In comparisons of the FDC group with the FDC + ICRF-187 group, clinical congestive heart failure was observed in 11 as compared with 2 patients; the mean decrease in the left ventricular ejection fraction was 7 vs. 1 percent when the cumulative dose of doxorubicin was 250 to 399 mg per square meter (P = 0.02), 16 vs. 1 percent at 400 to 499 mg (P = 0.001), and 16 vs. 3 percent at 500 to 599 mg (P = 0.003); and the Billingham biopsy score was 2 or more in 5 of 13 patients undergoing biopsy vs. none of 13 (P = 0.03). We conclude that ICRF-187 offers significant protection against cardiac toxicity caused by doxorubicin, without affecting the antitumor effect of doxorubicin or the incidence of noncardiac toxic reactions.

Recombinant Human Tumor Necrosis Factor Administered as a 24-Hour Intravenous Infusion. A Phase I and Pharmacologic Study

Abstract: Recombinant human tumor necrosis factor (rH-TNF) is a cytokine with direct antitumor properties. In a phase I trial we continuously infused rH-TNF for 24 hours. We gave a total of 115 courses of therapy to 50 patients. Doses ranged from 4.5 to 645 micrograms of rH-TNF/m2. Systemic toxicity, including fever, chills, fatigue, and hypotension, increased with the dose of rH-TNF administered. Doses greater than 454 micrograms/m2 frequently caused severe lethargy and fatigue, which precluded hospital discharge of the patient at the completion of therapy. The dose-limiting toxicity was hypotension, and five patients treated at the two highest dose levels required dopamine treatment. Other organ-specific toxicity was modest and spontaneously resolved after 48 hours. The 24-hour infusions of rH-TNF were associated with significant decreases in serum cholesterol and high-density lipoprotein levels. Pharmacokinetic studies using an enzyme-linked immunosorbent assay demonstrated peak plasma rH-TNF levels of 90-900 pg/mL. Despite continuous infusion of rH-TNF, no steady-state level was achieved. The recommended phase II dose for rH-TNF as a 24-hour continuous infusion is 545 micrograms/m2.

Recombinant human tumor necrosis factor administered as a five-day continuous infusion in cancer patients: phase I toxicity and effects on lipid metabolism.

Abstract: Recombinant human tumor necrosis factor (rH-TNF) is a cytotoxic monokine with pleiotropic effects. A phase I trial of rH-TNF was initiated using a five-day continuous intravenous (IV) infusion repeated every 28 days. Thirty-eight courses of therapy were administered to 19 patients. The starting dose was 5 X 10(4) U/m2/d, with escalations to 1.0 X 10(5), 2.0 X 10(5), 2.4 X 10(5), and 3.0 X 10(5) U/m2/d. Systemic side effects, including fever, chills, hypotension, fatigue, anorexia, and headaches, were mild and self-limiting. At the maximum tolerated dose of 3.0 X 10(5) U/m2/d, dose-limiting hematologic toxicity was manifested by transient thrombocytopenia and leukopenia. Elevated bilirubin levels were also seen at the higher dose levels. Lipoprotein analysis demonstrated that the five-day treatment with rH-TNF was associated with decreases in high-density lipoproteins, as well as increases in triglycerides and very-low-density lipoproteins. Pharmacokinetic studies using an enzyme-linked immunosorbent assay...

Catecholamine toxicity in cerebral cortex in dissociated cell culture.

Abstract: Identification of endogenous toxins and characterization of the mechanisms by which toxins produce cell injury and death may help understand both normal modeling of cell populations and connections in the CNS as well as abnormal cell loss The toxicity of catecholamines intrinsic to the CNS was investigated using the model system of rat cerebral cortex in dissociated cell culture All catecholamines tested, including norepinephrine (NE), dopamine, and epinephrine, were toxic to neurons as well as glia at a concentration of 25 microM when added to cultures 24 hr after plating Toxicity was evident after 48 hr exposure to NE, as monitored by loss of cells from the cultures Toxicity did not seem to be mediated by adrenergic receptors because, although the beta-adrenergic agonist isoproterenol (but not the alpha-adrenergic agonist phenylephrine) was similar in its toxic effect to NE, the beta- adrenergic antagonist atenolol did not block the toxic effect of NE Toxicity could be mimicked by hydrogen peroxide, a product of the oxidative degradation of catecholamines Toxicity of NE was blocked by catalase The neurotoxin 6-hydroxydopamine (6-OHDA), supposedly selective for catecholaminergic neurons, was found to be toxic over the same concentration range as NE These results suggest that endogenous catecholamines may play a role in normal and abnormal cell death, and suggest that caution be used in relying on the specificity of 6-OHDA and other supposedly selective neurotoxins

Pulmonary Function and Symptom Responses after 6.6-Hour Exposure to 0.12 ppm Ozone with Moderate Exercise

Abstract: Episodes occasionally occur when ambient ozone (O3) levels remain at or near 0.12 ppm for more than 6 h. Small decrements In lung function have been reported following 2-h exposures to 0.12 ppm O3. For short exposures to higher O3 concentrations, lung function decrements are a function of exposure duration. Thus, we investigated the hypothesis that prolonged exposure to 0.12 ppm O3 would result in progressively larger changes in respiratory function and symptoms over time. Ten nonsmoking males (18-33 yr) were exposed once to clean air and once to 0.12 ppm O3 for 6.6 h. Exposures consisted of six 50-min exercise periods, each followed by 10-min rest and measurement; a 35-min lunch period followed the third exercise period. Exercise ventilation averaged approximately 40 L/min. Forced expiratory and inspiratory spirometry and respiratory symptoms were measured prior to exposure and after each exercise. Airway reactivity to methachollne was determined after each exposure. After correcting for the air exposure...

Neuronal death in vitro: parallelism between survivability of hippocampal neurones and sustained elevation of cytosolic Ca2+ after exposure to glutamate receptor agonist.

Abstract: Hippocampal neurones isolated from rat embryos were maintained on glial monolayers in a medium containing no L-glutamate (Glu). The administration of Glu for a limited period induced a massive death (loss) of neurones. The degree of neuronal loss increased with time after exposure to Glu. The extent of neuronal loss assessed 24 h after exposure to Glu was dependent upon the concentration Glu and on the duration of the exposure. An increase in concentration of external Ca2+ during the exposure to Glu enhanced the extent of loss. By contrast, an increment in concentration of environmental Mg2+ reduced the loss. The inhibitor of spike firing, tetrodotoxin (TTX) and the suppressor of Ca2+ entry, nitrendipine, both decreased the extent of loss, when delivered prior to Glu. The toxicity of Glu became progressively more apparent with further days of culture. The cytosolic concentration of Ca2+ ([Ca2+]i) in single hippocampal neurones was monitored by microscopic fluorometry under conditions equivalent to those in the death assay. The time required for the recovery of [Ca2+]i from the level elevated by exposure to Glu to pre-stimulus levels closely paralleled the degree of neuronal loss; i.e. high doses of Glu, long periods of exposure, high concentrations of external Ca2+, low concentrations of external Mg2+, and extended days of culture all retarded [Ca2+]i recovery, while TTX and nitrendipine accelerated it. These findings show that neuronal death resulting from an extraneous excitation (excitotoxicity) can be analyzed in vitro. Furthermore, substantial support has been provided to the hypothesis that excitotoxicity has as an underlying mechanism, an excess loading of Ca2+ in neuronal cytoplasm.

Toxicity and metabolism of pyrrolizidine alkaloids

Abstract: Pyrrolizidine alkaloids (PA) are found mainly in plants of three families: boraginaceae, Compositae and Leguminosae. In North America, PA poisoning of livestock is caused primarily by consumption of Senecio and Crotalaria spp. The PA of Senecio spp. cause irreversible hepatic damage; toxicity signs are a consequence of impaired liver function. Crotalaria intoxication leads to pulmonary damage as a primary effect; hepatic effects are less prominent. Large species differences exist in susceptibility to PA toxicosis. Small herbivores such as sheep, goats, rabbits, guinea pigs and other herbivorous laboratory animals are highly resistant to PA toxicity, associated with a low rate of hepatic production of reactive metabolites (pyrroles) and(or) a high rate of activity of detoxifying enzymes. Diester PA common to Heliotropium and Echium spp. are metabolized in the ovine rumen to 1-methyl metabolites, whereas the macrocyclic ester PA of Senecio spp. are not. Exposure to PA results in high concentrations of liver Cu, reduced liver Zn, and abnormal Fe metabolism with hematopoiesis markedly impaired. Pyrrolizidine alkaloid toxicity alters vitamin A metabolism in rats, depressing plasma and liver levels of vitamin A. Synthetic antioxidants in the diet confer protective activity in laboratory animals (e.g., rats, mice) against PA toxicoses. The PA and their metabolites are secreted in the milk of lactating animals, but this probably does not represent a significant human health hazard.

Phase I trial of a mouse monoclonal antibody against GD3 ganglioside in patients with melanoma: induction of inflammatory responses at tumor sites.

Abstract: Twenty-one patients were entered into a phase I trial to evaluate toxicity, antitumor effects, and biological responses at tumor sites during treatment of R24, an immunoglobulin G3 (IgG3) mouse monoclonal antibody (mAb) against GD3 ganglioside. Toxicity was related to dose of R24. Urticaria and pruritus were the most prominent side effects, with nausea, vomiting, and diarrhea occurring at the highest dose levels. Partial responses were observed in four patients lasting from 6 to 46 weeks, and mixed responses were seen in two patients. Responses occurred as early as 4 weeks and as late as 10 weeks after beginning treatment. Twenty of the 21 patients developed human IgG antibodies against R24. Antimouse Ig antibodies were first detected at a median of 14 days after starting treatment, but three of the four patients who had a partial response developed the antimouse Ig responses later than 20 days. Peak serum levels of R24 were related to dose and ranged from a mean of 0.9 micrograms/mL at the lowest dose le...

Synthesis and in vitro toxicity of hydroxylamine metabolites of sulfonamides.

Abstract: Among the most serious side effects of sulfonamides are hypersensitivity reactions, the pathogenesis of which has been suggested to be mediated by reactive metabolites. We have previously demonstrated dose-related covalent binding and toxicity of reactive intermediates of sulfonamides generated by a murine hepatic microsomal activating system. We hypothesized that hydroxylamine (H/A) metabolites might be likely candidates for mediating such toxicity; accordingly, we synthesized chemically the H/As of sulfadiazine and sulfamethoxazole. Synthesis was performed using 4-nitrobenzenesulfonyl chloride and either 2-aminopyrimidine or 3-amino-5-methylisoxazole, respectively, as starting materials. The resulting nitro derivatives were reduced to the corresponding H/A with hydrogen in the presence of a poisoned platinum catalyst. After synthesis and purification, toxicity of the H/As to lymphocytes of normal volunteers was evaluated using three cytotoxicity assays: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide dye conversion, trypan blue dye exclusion and propidium iodide dye exclusion. The H/As of sulfadiazine and sulfamethoxazole displayed dose-related toxicity. 1.6 mM sulfadiazine H/A produced 82% cell death, whereas 400 microM sulfamethoxazole H/A produced 62% cell death; the parent sulfonamides were not toxic to cells. The toxicity of sulfamethoxazole H/A was decreased by coincubation with glutathione or N-acetylcysteine; there was a 47% decrease in toxicity when coincubated with 100 microM glutathione, whereas there was a 55% decrease displayed when coincubation was done with 500 microM N-acetylcysteine. H/A metabolites of the sulfonamides or their nitroso derivatives, normally detoxified by conjugation to glutathione, may be the proximate toxins mediating sulfonamide hypersensitivity.

Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis.

Abstract: The pharmacokinetics of fluconazole, a new oral azole, were evaluated in cerebrospinal fluid and sera of eight patients with coccidioidal meningitis. At a dose of 50 mg/day, peak concentrations of 2.5 to 3.5 and 2.0 to 2.3 micrograms/ml occurred at 2 to 6 and 4 to 8 h in serum and cerebrospinal fluid, respectively. At 100 mg/day, peak concentrations of 4.5 to 8.0 and 3.4 to 6.2 micrograms/ml occurred at 2 to 4 and 4 to 12 h, respectively. The mean ratios of the concentration in cerebrospinal fluid to that in serum were 73.8% at 50 mg/day and 88.7% at 100 mg/day. Results suggested that there was a prolonged half-life in both cerebrospinal fluid and serum and that it was slightly longer in the former. Minimal toxicity was noted in 34 patient months of therapy (12 months on 50 mg daily; 22 months on 100 mg daily). After a mean of 4.5 months of therapy, five patients responded to therapy and three were unevaluable. The penetration of fluconazole into cerebrospinal fluid was substantial, toxicity was minimal, and early clinical experience was encouraging. Fluconazole holds promise as the sole or adjunctive therapy for fungal meningitis.

Oral toxicity of a bloom of the Cyanobacterium microcystis Aeruginosa administered to mice over periods up to 1 year.

Abstract: Cyanobacterial blooms in lakes have been reported causing livestock deaths and liver injury to human populations. In this study bloom material consisting of Microcystis aeruginosa was collected from a farm water storage after the death of sheep drinking from it. The cyanobacterial cells were lysed and a cell-free extract was provided to mice at a series of dilutions as their only source of drinking water. Mice of both sexes, with controls, were killed at intervals up to 1 yr of administration. Autopsies, histopathological examination, and analyses of plasma lactate dehydrogenase and alanine aminotransferase were carried out. Increased mortality was observed, particularly among males, together with chronic active liver injury and elevated alanine aminotransferase in blood. In control mice and those receiving lower concentrations of extract, hepatic amyloidosis with neutrophil infiltration, and bronchopneumonia, were seen with increasing age. The bronchopneumonia appeared earlier among mice receiving cyanobacterial extract. Four tumors were seen in 71 mice receiving a high concentration of extract for up to 1 yr, none in 150 mice receiving lower concentrations, and 2 in 73 control mice. No effects on male or female fertility, embryonic mortality, neonatal viability, or skeletal development were observed, but 7 out of 73 neonatal mice born to parents given cyanobacterial extract showed reduced brain size. No cases were seen in controls. We conclude that the major toxicity exhibited is liver injury. Further attention is needed for evaluation of carcinogenicity and embryonic damage.

Cyclosporine, low-density lipoprotein, and cholesterol.

Abstract: Lipoproteins are known to be able to transport a variety of drugs. This report suggests that low-density lipoprotein not only functions as an important carrier of cyclosporine in plasma but also facilitates transport of cyclosporine across the cell membrane by means of the low-density lipoprotein receptor. Such a mechanism would explain (1) the similar tissue distribution of cyclosporine and the low-density lipoprotein receptor, (2) the increase in immunosuppression and toxicity with low total serum cholesterol levels, and (3) the relative absence of immunosuppression and toxicity with high levels of cyclosporine in the blood in patients with hypertriglyceridemia. In addition to receptor-mediated uptake, a disturbance of the blood-brain barrier is suggested as an explanation of the high frequency of cyclosporine-induced central nervous system toxicity after liver transplantation. Cyclosporine-induced inhibition of the mitochondrial steroid 26-hydroxylase, an enzyme involved in the formation of bile acids from cholesterol and deficient in patients with cerebrotendinous xanthomatosis, may cause or contribute to the observed central nervous system toxicity. It also may explain the similar clinical features of cyclosporine-induced central nervous system toxicity and cerebrotendinous xanthomatosis.

Toxicity and 7-ethoxyresorufin O-deethylase-inducing potency of coplanar polychlorinated biphenyls (PCBs) in chick embryos.

Abstract: The toxicities of the coplanar polychlorinated biphenyls 3,3′,4,4′-tetrachlorobiphenyl (TCB), 3,3′,4,4′,5-pentachlorobiphenyl (PeCB) and 3,3′,4,4′,5,5′hexachlorobiphenyl (HCB) were compared in a 72-h study on chick embryos. The substances were injected into the air sacs of hens' eggs preincubated for 7 days. Mortality was measured 72 h later and corresponding LD50 values were calculated. The rank order of toxicity was PeCB> TCB>HCB. Using the same injection procedure, the potencies of these chlorobiphenyls with regard to their induction of hepatic 7-ethoxyresorufin O-deethylase activity were compared. The ranking order of the substances as inducers was the same as their order when ranked according to toxicity. The three coplanar chlorobiphenyls were considerably more toxic and potent as inducers than the nonplanar 2,2′,4,4′,5,5′-hexachlorobiphenyl. In a 2-week toxicity study, PeCB and HCB were injected into the yolks of hens' eggs preincubated for 4 days. PeCB was about 50-fold more potent than HCB in causing embryonic death. Both substances caused abnormalities, including edema, liver lesions, microphthalmia and beak deformities.

Influence of dose and duration of infusion of interleukin-2 on toxicity and immunomodulation.

Abstract: The purpose of this study was to investigate the effect of dose and duration of infusion of recombinant interleukin-2 (IL-2) on toxicity and immunomodulation. In a phase I/II study, IL-2 was administered intravenously (IV) daily for five consecutive days every other week for 4 weeks of treatment to 23 patients with progressive melanoma, renal, colon, or ovarian cancer by one of four regimens: groups I and II received 3 X 10(5) U/m2/d by two-hour or 24-hour infusion, respectively; groups III and IV received 3 X 10(6) U/m2/d by two-hour or 24-hour infusion, respectively. In a subsequent study, six patients (group V) received a single priming cycle of daily IL-2 for five days at 3 X 10(6) U/m2/d in divided 15-minute infusions every eight hours, before undergoing leukapheresis for lymphokine-activated killer (LAK) cell generation. Toxicity was mild with 3 X 10(5) U/m2/d, but severe chills and fever, moderate hypotension (not requiring IV pressors), and weight gain were observed with 3 X 10(6) U/m2/d. Toxicity...

Effects of SO2 exposure on allergic sensitization in the guinea pig.

Abstract: The effect of sulfur dioxide (SO 2 ) exposure on local bronchial sensitization to inhaled antigen was studied in the guinea pig. Exposure to SO 2 (0.1 to 16.6 ppm) was performed in a 20 L exposure chamber for 8 hours on 5 consecutive days, while temperature, moisture, and concentration of SO 2 were monitored and kept constant. SO 2 concentrations were measured hourly by Schiff's reaction. On the last 3 days, SO 2 exposure was followed by inhalation of nebulized ovalbumin (OA) for 45 minutes. One week later, specific bronchial provocation with inhaled OA (0.1%) followed by plethysmographic measurements of airway obstruction were performed every 2 days during a 2-week period. Specific antibodies against OA were measured in serum and bronchoalveolar fluid by a direct enzyme immunoassay. The SO 2 -exposed group (N = 17) demonstrated 67% to 100% positive bronchial reactions to inhaled OA, depending on the concentration of SO 2 , whereas the control group without previous SO 2 exposure (N = 14) demonstrated bronchial reactions in only one animal (7%: p 2 concentrations ( p 2 -exposed groups significantly, compared to the control group ( p 2 in low and medium concentrations can facilitate local allergic sensitization in the guinea pig.

Mechanisms of mutagenicity and toxicity of sodium selenite (Na2SeO3) in Salmonella typhimurium

Abstract: The mechanisms of selenite toxicity and mutagenicity in S typhimurium have been characterized In contrast to previous reports, selenite toxicity was shown not to involve nonspecific incorporation into protein via the sulfur metabolic pathways Selenite toxicity was, however, shown to involve its ability to act as an oxidizing agent, primarily through reactions with sulfhydryls Strains which lack glutathione (GSH) are more sensitive to killing by sulfhydryl reagents The selenite sensitivity of such a mutant was a biphasic phenomenon The mutant was much more sensitive than a strain which contained GSH at lower selenite concentrations whereas, at higher concentrations, the mutant was much more resistant to selenite The mechanism of selenite toxicity at lower concentrations in this mutant thus appeared to involve damage to intracellular sulfhydryls The sensitization to higher doses of selenite by GSH could be explained by the generation of toxic oxygen species The in vitro reactions of selenite with both cysteine and GSH readily produced H2O2 and O2- A S typhimurium strain which overproduces superoxide dismutase (SOD) and catalase was more resistant to high concentrations of selenite, but not killing by the lower doses Pretreatment of cells with a nonlethal dose of selenite induced the synthesis of proteins which protected the cells from killing by H2O2 or high doses of selenite Selenite was also a mutagen in the tester strain TA104, in which a number of other oxidizing agents have also been found to be mutagens These results were consistent with a model in which the reactions of selenite and intracellular thiols with concomitant production of active oxygen species are the primary causal agents of selenite mutagenicity and toxicity in S typhimurium

Combined effects of chemotherapy and interleukin 2 in the therapy of mice with advanced pulmonary tumors.

Abstract: We have evaluated the effects of chemotherapeutic agents on the toxicity and antitumor benefit of therapy of established murine tumors by high-dose interleukin 2 (IL-2). Cyclophosphamide (Cy), doxorubicin, and bischloroethylnitrosourea were given to normal mice prior to IL-2 administration to test the effects of these agents on IL-2-induced toxicity. Cy at doses of 100 mg/kg and 150 mg/kg completely protected mice from a 100% lethal dose of IL-2, and doses of 50 mg/kg and 150 mg/kg allowed the administration of a median of 4.5 and 10.0 more doses of IL-2, respectively, before death from IL-2 toxicity occurred. Doxorubicin at 8 mg/kg and bischloroethylnitrosourea at 20 mg/kg did not impact on toxicity in IL-2-treated mice. In mice bearing pulmonary metastases of the weakly immunogenic MCA-105 sarcoma, IL-2 increased median survival time from 33 (no IL-2) to >60 days for all doses of IL-2 tested when combined with a single injection of Cy at 75 mg/kg ( P in vivo generated lymphokine-activated killer cells, but these lymphokine-activated killer cells are still lytic for fresh tumor targets in vitro . Thus, the mechanism of this synergy does not appear to involve stimulation of lymphokine-activated killer cell activity, but may in part involve reduction of tumor burden by the chemotherapeutic agent, an increase in susceptibility of tumor to cellular immune lysis, and/or a decrease in suppressor cell activity mediated by the chemotherapy.

Toxicity of polymerized hemoglobin solutions.

Abstract: Four solutions of bovine polymerized hemoglobin (BPHS) and rabbit plasma were used to replace one-third of the blood volume in five groups of rabbits. The first three solutions were "impure" because of the presence of stromal phosphatidyl-ethanolamine and phosphatidyl-serine in BPHS-1, environmental endotoxins in BPHS-2, and a large amount of higher molecular weight hemoglobin-glutaraldehyde polymers in BPHS-3. These solutions caused a 33 per cent mortality rate and significant morbidity which was characterized by hemodynamic instability, respiratory and renal insufficiency, elevation of hepatic enzyme levels, thrombocytopenia, leukopenia, disseminated intravascular coagulation (DIC) and activation of the alternate pathway of complement. Histopathologic changes found in the heart, lungs, liver, spleen and kidney were characterized by a combination of ischemic and inflammatory lesions. Fibrin thrombi were visible by immunofluorescence in the microcirculation. In contrast, the fourth solution (BPHS-4) was free of the aforementioned impurities; caused no deaths and minimal morbidity, which was limited to elevated levels of serum glutamic pyruvic transaminase and reduction of creatinine clearance; no DIC or complement activation, and mild histopathologic changes which were exclusively ischemic in nature. The results of this study indicated that the toxicity of polymerized hemoglobin solutions is due principally to the presence of impurities. Pure hemoglobin does exhibit mild toxicity when compared with a control solution which is most likely due to a vasoconstrictor effect of oxyhemoglobin.

Role of leukotrienes in acute gastric lesions induced by ethanol, taurocholate, aspirin, platelet-activating factor and stress in rats.

Abstract: This study was designed to determine the role of leukotriene C4 (LTC4) in the formation of acute gastric lesions induced by 100% ethanol, acidified taurocholate (TC), acidified aspirin (ASA), platelet-activating factor (PAF), and water-immersion and restraint stress. Exogenous LTC4 alone administered in gradually increasing doses (5–20μg/kg/hr) caused only mild hemorrhagic lesions in the gastric mucosa but when combined with 100% ethanol, acidified TC, acidified ASA, or stress, it increased significantly the mean lesion area and lesion number as compared to those produced by these ulcerogens alone. FPL 55712, a LTC4 antagonist, given orally (2.5–10 mg/kg) reduced dose-dependently the extent of gastric lesions in all experimental models used and completely prevented the deleterious effects of exogenous LTC4 on gastric mucosa. PAF augmented the mucosal lesions induced by 100% ethanol, and this was also reduced by the pretreatment with FPL 55712. FPL 55712-induced gastroprotection against various ulcerogens was reversed, in part, by indomethacin, indicating that it could be attributed not only to the LTC4 antagonism but also to increased biosynthesis of PGs. This study provides evidence that LTC4 is involved in the formation of acute gastric damage and the antagonism of LTC4 may protect the mucosa against various ulcerogens.